The research to be undertaken is directed at improving our understanding of lipid and lipoprotein metabolism as it relates to atherosclerosis. The mechanisms regulating steady-state levels of plasma lipoproteins and the mechanisms involved in the transport of lipoproteins into and out of cells will be studied using in vivo systems, organ perfusion systems and cell culture systems. Clinical studies will emphasize comparison of lipoprotein metabolism in patients with various forms of inherited hyperlipoproteinemia. Both lipid and protein turnover will be examined and sterol balance will be concurrently measured in each case. The effects of diets and drugs on lipoprotein metabolism and sterol metabolism will be studied with a view to establishing mechanisms of action and safety. Cell culture techniques will be broadly applied (aortic smooth muscle and endothelial cells, fibroblasts, hepatocytes). The basic mechanisms involved in the uptake and degradation of lipoproteins will be studied. The hepatocyte culture system will be used to define factors regulating the biosynthesis and secretion of very low density lipoproteins. Finally, studies on the influence of lipoproteins on hepatocyte cell growth will be carried out, attempting to identify the factor or factors responsible for this action. The supplemental program proposed will extend studies of tissue sites of lipoprotein degradation utilizing a new approach recently developed in this laboratory and already validated for LDL. Sites of HDL apoprotein A-1 degradation and sites of HDL apoprotein E degradation are to be studied in swine and in rats and, time and funds allowing, also apoprotein C components. The latter studies will be under the direction of Dr. Joseph L. Witztum who has recently joined the La Jolla SCOR program. Included in the supplemental proposal are two new clinical research projects. 1) The first is directed at elucidating the changes in lipoprotein metabolism that occur after ileal bypass (in collaboration with Dr. John J. Coyle, newly arrived at UCSD).